Synthetic transformations from chiral pool precursors
such as carbohydrates generally lead to the formation of
optically active products. However, it was surprising for
us to obtain racemic products under the present reaction
conditions. Though exceptional, it was yet considered
advantageous, as both the enantiomers can be obtained
through kinetic resolution using the literature procedures.10
Especially, concomitant nucleophilic substitution at the
R-position is the most significant outcome of the present
domino reaction. Besides, the racemic R-substituted furan
moiety can be directly utilized in the preparation of
antibiotics such as (()-1-deoxygulonojirimycin1a and (()-
mannojirimycin.2b
Scheme 2
.
Syntheses of R-Substituted ꢀ-Hydroxyfurfuryl
Derivatives in the Literature
For optimization, catalytic efficacies of various Lewis
acids were screened for the desired conversions (see
Supporting Information, Table 1). It was observed that
In(OTf)3 in acetonitrile (1 mol %) was superior to other
catalysts with regard to yield, reaction time, and minimal
side product formation (2, 4). High regioselectivity was
observed in polar aprotic solvents, and acetonitrile was
found to be the best (see Table 2 in Supporting Informa-
tion). Substituting methanol with an aprotic nucleophile
such as TMSN3 yielded (()-2-hydroxy-1-(2-furyl)ethyl
azide (3o), an important intermediate for many azasugar
antibiotics,2d as the major product (80%) (Table 1 entry
15). It may be noted that Vincent et al. failed to obtain
such a product while working with R-furyl benzyl alcohol
and TMSN3.5 The nucleophilic substitution reaction with
TMSN3 can also be carried out smoothly in water with
longer reaction time. Besides, the reaction could also be
catalyzed by montmorillonite KSF or H2SO4 on silica at
an elevated temperature (80 °C) to yield 3o, though in
poor yield. Likewise, D-galactal also readily reacted with
this reagent system, forming 3o in 72% yield in 1 h.
After establishing the reaction protocol, we further
explored the scope and the generality of the method using
various O, S, or N nucleophiles (see Supporting Informa-
tion, Figure 1) for the preparation of a small library of
furfuryl analogues 3a-o. The free amine, however, failed
to react at all (entry 14). As expected, the thiols reacted
faster than the alcohols and all the reactions were
completed within 20 min, requiring less than 1 mol % of
the catalyst. The electronic nature of the nucleophiles
seems to have a modest influence on the rate of the
reaction (Table 1, entries 10-13). It was also observed
that the use of alcohols larger than methanol generally
led to an increase in the formation of R-substituted
products (Table 1, entries 2-7). Significantly, with
earlier attempts at Lewis acid catalyzed R-substitution of
furfuryl derivatives by direct nucleophilic attack was not
successful due to the degradation of the acid-sensitive
furfuryl residue.5 The development of a more flexible and
direct approach for the construction of a furfuryl scaffold is
therefore highly desirable. Our group, which has been
involved in synthesizing orthogonally protected building
blocks from carbohydrate precursors,6 now reports the
development of a short and rapid one-pot domino chemose-
lective synthesis of racemic furfuryl derivatives from D-
glucal.
Acid-catalyzed transformation of D-glucal to optically
active furan diol7 is a well-studied reaction. Nucleophilic
attack of water on D-glucal was proposed to be the possible
mechanism.7c Under similar conditions, L-rhamnal gave a
complex mixture of optically inactive furan tetramers.7e On
the other hand, a protected glycal undergoes Ferrier rear-
rangement8 and a partially protected glycal follows an
addition pathway when reacted with nucleophiles in presence
of Lewis acid.9 However, the behavior of nucleophiles
toward unprotected glucal has not been studied in details.
The only report available to date describes prolonged
treatment of D-glucal with methanolic HCl, which resulted
in the formation of a racemic furan derivative, i.e., 2-hy-
droxymethyl-5-methoxy furan in poor yield.7h
We, therefore, envisaged that a nucleophile other than
water may deliver a different type of product with an
unprotected glucal. Accordingly, glucal was stirred in ac-
etonitrile using methanol as a nucleophile under standard
Lewis acid conditions at ambient temperature. Surprisingly,
no methyl glycoside formation was observed. Instead, a
mixture comprising two racemic compounds and a minor
optically active furan diol 2 was obtained (Scheme 3). The
(3) Brown, R. C. D. Angew. Chem., Int. Ed. 2005, 44, 850–852.
(4) (a) Xin, C.; Ke-Gang, L.; Qing-Jiang, L.; Zhu-jun, Y. Tetrahedron
Lett. 2005, 46, 8567–8571, and references therein. (b) Porzelle, A.; Gardon,
V. A.; Williams, C. M. Synlett 2007, 1619–1621. (c) Koulocheri, S. D.;
Haroutounian, S. A. Synthesis 1999, 1889–1892. (d) Yang, J. W.; Chandler,
C.; Stadler, M.; Kampen, D.; List, B. Nature 2008, 452, 453–455. (e) Liao,
L.-X.; Wang, Z.-M.; Zhang, H.-X.; Zhou, W. S. Tetrahedron: Asymmetry
1999, 10, 3649–3657. (f) Alcaide, B.; Biurrum, C.; Plumet, J. Tetrahedron
1992, 48, 9719–9724.
Scheme 3. Unexpected Reaction of D-Glucal with Methanol
(5) Tarrasson, V.; Marque, S.; Georgy, M.; Campagne, J.-M.; Prim, D.
AdV. Synth. Catal. 2006, 348, 2063–2067.
major product was identified as a racemic R-furfuryl deriva-
(6) Mukherjee, D.; Shah, B. A.; Gupta, P.; Taneja, S. C. J. Org. Chem.
2007, 72, 8965–8968.
1
tive 3a from the H NMR spectrum.
4832
Org. Lett., Vol. 10, No. 21, 2008
Mukherjee, Debaraj
